Cytotoxic, DNA binding and drug reservoir property of Pt(II)–sulfur complexes: In-vitro kinetics, mechanism with bio-relevant molecules in aqueous medium and a theoretical approach

Abstract

Synthesis and cytotoxic property of Pt(II)-sulfur complexes are significant in biological aspect. In order to investigate their relevance, two sulfur chelated model complexes are considered for detailed study. Invitro drug reservoir property of the complex [Pt(MAMP)(H2O)2]X22 (where, MAMP = 2-[(N-methylamino) methyl]pyridine and X = NO3_ or ClO4_) in model reactions with sulfur containing bio-molecules dl-methionine (dl-meth) and dl-penicillamine (dl-pen) are studied to explore the 'drug reservoir' mechanism. The complex [Pt(MAMP)(dl-meth)] 3 and [Pt(MAMP)(dl-pen)] 4 are synthesized from complex 2, which is obtained from the hydrolysis of complex [Pt(MAMP)Cl2] 1 and characterized by spectroscopic methods. Interaction mechanism between complex 2 with dl-meth and dl-pen has been established by kinetic study. Two step consecutive reaction rate constants (k1 and k2) and corresponding activation parameters (DH_ and DS_) for both the steps are calculated and an associative mechanism is proposed. Theoretical investigations like structural optimization, HOMO-LUMO energy calculations, NBO analysis have been performed. The coordination mode of dl-meth and dl-pen via (S, O) are established by spectroscopic methods and confirmed by NBO analysis. DNA binding property of the complexes 2-4 has been investigated by UV-Vis spectra, competitive binding experiment, gel electrophoresis and their corresponding binding constants (kb and ksv) are calculated. The computational molecular docking study is carried out for the complexes with B-DNA to confirm their DNA binding mode. Cytotoxic property of the complexes 3 and 4 are investigated on HeLa and HepG2 cell lines and also been compared with complex 2 and well known anticancer drug cisplatin and their corresponding IC50 values are calculated. _ 2016 Elsevier Ltd. All rights reserved